title: AICAR stimulation metabolome widely mimics electrical contraction in isolated rat epitrochlearis muscle.
abstract: Physical exercise has potent therapeutic and preventive effects against metabolic disorders. A number of studies have suggested that 5'-AMP-activated protein kinase (AMPK) plays a pivotal role in regulating carbohydrate and lipid metabolism in contracting skeletal muscles, while several genetically manipulated animal models revealed the significance of AMPK-independent pathways. To elucidate significance of AMPK and AMPK-independent signals in contracting skeletal muscles, we conducted a metabolomic analysis that compared the metabolic effects of 5-aminoimidazole-4-carboxamide-1-β-D-ribonucleoside (AICAR) stimulation with the electrical contraction ex vivo in isolated rat epitrochlearis muscles, in which both α1- and α2-isoforms of AMPK and glucose uptake were equally activated. The metabolomic analysis using capillary electrophoresis time-of-flight mass spectrometry detected 184 peaks and successfully annotated 132 small molecules. AICAR stimulation exhibited high similarity to the electrical contraction in overall metabolites. Principal component analysis (PCA) demonstrated that the major principal component characterized common effects whereas the minor principal component distinguished the difference. PCA and a factor analysis suggested a substantial change in redox status as a result of AMPK activation. We also found a decrease in reduced glutathione levels in both AICAR-stimulated and contracting muscles. The muscle contraction-evoked influences related to the metabolism of amino acids, in particular, aspartate, alanine, or lysine, are supposed to be independent of AMPK activation. Our results substantiate the significance of AMPK activation in contracting skeletal muscles and provide novel evidence that AICAR stimulation closely mimics the metabolomic changes in the contracting skeletal muscles.
authors.affiliation: Laboratory of Pharmacology and Physiological Sciences, Frontier Laboratory for Pharmaceutical Sciences, Institute of Health Biosciences, University of Tokushima Graduate School, Sho-machi, Tokushima, Japan;
authors.forename: Licht
authors.initials: L
authors.lastname: Miyamoto
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Egawa
authors.forename: Rieko
authors.initials: R
authors.lastname: Oshima
authors.forename: Eriko
authors.initials: E
authors.lastname: Kurogi
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Tomida
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Hayashi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D004558:Electric Stimulation; D005163:Factor Analysis, Statistical; D005947:Glucose / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D055442:Metabolome; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000502:physiology; D025341:Principal Component Analysis; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012265:Ribonucleotides / Q000494:pharmacology*; D059467:Transcriptome
chemical_list: D007004:Hypoglycemic Agents; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D005978:Glutathione; D005947:Glucose
keywords: 5′-AMP-activated protein kinase; AICAR; isolated skeletal muscle; metabolome; muscle contraction